Inflammatory lung diseases such as asthma affect nearly 300 million people worldwide, including approximately 11% of the U.S. population. Currently, chronic inflammatory lung diseases can be controlled, but not cured; thus placing them among the most expensive diseases for long-term healthcare. A hallmark of chronic airway inflammation is the increase in cytokines that provoke inflammation in the lung and airway hyper-responsiveness. Current therapies revolve around the use of corticosteroids for suppression of inflammation, which while effective, have significant side effects. A potentially powerful approach would be small molecule manipulation of the cytokine response. The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor belonging to the Per-ARNT-SIM (PAS)-basic-helix-loop-helix (bHLH) protein family that modulates immune cell differentiation and function in response to natural and synthetic ligands. The AhR interacts with structurally diverse ligands resulting in differential effects on cytokine secretion by innate lymphoid cells (ILCs). Our preliminary results support the premise that functional differences in AhR ligands may be exploited to manipulate the expression of regulatory (e.g. IL-22) vs. inflammatory (e.g. IL-17) cytokines in airway inflammation, thus reducing it. If we can design small molecules that selectively induce IL-22 production by group 3 ILCs, it should be possible to promote this effect, and use this knowledge to develop novel therapies for inflammatory lung diseases. Therefore, this project will focus on understanding the mechanisms by which YH439 and custom-designed analogs activate the AhR and induce the expression of IL-22 in ILCs, leading to a non-toxic immune- modulatory action. We will then create a novel photoaffinity probe for the purposes of: 1) interrogating AhR- ligand interactions, 2) elucidating AhR structure, function, and conformation changes, and 3) identifying novel or alternative binding sites in proteins. The results generated from the successful completion of this project are expected to support the concept that modulation of AhR signaling pathways in the lungs impacts the progression of inflammatory diseases by altering the functional capacity of ILCs.